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[Exploring the mechanism of HIV infection on T lymphocyte mitochondrial damage based on MAPK pathway]
Yong Deng1, Cheng Chen2, Zhong Chen1
1Department of Infection and Immunology, Changsha First Hospital, Changsha 410005, China.
Abstract:
Objective To clarify the mechanism that HIV infection mediates mitochondrial damage of CD4+ T lymphocytes (CD4+ T cells) through mitogen-activated protein kinase (MAPK) pathway. Methods From October 1st, 2022 to March 31st, 2023, 47 HIV-infected people who received antiretroviral therapy (ART) for 4 years were recruited, including 22 immune non-responders (INR) and 25 responders (IR); and 26 sex and age-matched control participants (HC) who were negative for HCV, HBV, and HIV infections. The immune parameters were analyzed by flow cytometry. Finally, peripheral blood mononuclear cells (PBMCs) from HC or HIV patients were treated with MAPK pathway inhibitor SB203580, and the changes of mitochondrial function of CD4+ T cells were observed. Results Compared with HC group, the proportion of CD4+ T cells in PBMCs in INR group and IR group was significantly lower, and the proportion of CD4+ T cells in PBMCs in INR group was significantly lower than that in IR group. In addition, the proportion of naive (CD45RA+CD27+)T cells in PBMCs in INR group was significantly lower than that in HC group and IR group. Compared with HC group and IR group, the proportions of CD4+PD-1+, CD4+Av+ and CD4+MO+ in PBMCs in INR group and the proportions of CD45RA+CD27+PD-1+, CD45RA+CD27+Av+, CD45RA+CD27+MO+ in CD4+ T cell subsets increased significant. Compared with HC-con group, the basal respiration, maximal respiration and adenosine triphosphate(ATP) production of CD4+ T cells in HIV-con group decreased significantly, and JC-1 (green/red) in CD4+ T cells increased significantly. Compared with HIV-con group, the basal respiration, maximal respiration, ATP production and respiratory potential of CD4+ T cells in HIV-SB203580 group increased significantly, and the JC-1 (green/red) in CD4+ T cells decreased significantly. Conclusion Abnormal activation of the MAPK signaling pathway is observed in HIV patients receiving ART treatment, especially in CD4+ T cells of INR patients, which may lead to impaired mitochondrial function and abnormal CD4+ T cell homeostasis.
Insights
Abnormal mitogen-activated protein kinase (MAPK) pathway activation in HIV patients on antiretroviral therapy (ART) damages CD4+ T cell mitochondria, particularly in immune non-responders (INR). This impairs immune function and highlights MAPK as a therapeutic target.
Area of Science:
- Immunology
- Cell Biology
- Virology
Context:
- HIV infection leads to CD4+ T cell depletion and dysfunction.
- Antiretroviral therapy (ART) controls viral load but immune recovery can be incomplete, especially in immune non-responders (INR).
- Mitochondrial damage is implicated in CD4+ T cell dysfunction in HIV.
Purpose:
- To investigate the role of the mitogen-activated protein kinase (MAPK) signaling pathway in mediating mitochondrial damage in CD4+ T cells of HIV-infected individuals.
- To compare immune parameters and mitochondrial function in HIV-infected individuals with different responses to ART and healthy controls.
- To assess the effect of MAPK pathway inhibition on CD4+ T cell mitochondrial function.
Summary:
- HIV patients on ART, particularly INR, exhibit reduced CD4+ T cell counts and altered T cell subsets.
- Abnormal MAPK pathway activation correlates with increased expression of PD-1, Av, and MO markers on CD4+ T cells in INR patients.
- HIV infection impairs CD4+ T cell mitochondrial respiration and ATP production, effects reversed by MAPK inhibition (SB203580).
Impact:
- Abnormal MAPK signaling contributes to mitochondrial dysfunction and CD4+ T cell homeostasis disruption in HIV patients on ART.
- Targeting the MAPK pathway may offer a novel therapeutic strategy to restore CD4+ T cell function and improve immune recovery in HIV.
- Findings provide insights into the mechanisms underlying immune non-response to ART in HIV infection.
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